A novel potent metal-binding NDM-1 inhibitor was identified by fragment virtual,SPR and NMR screening

NDM-1 can hydrolyze nearly all available β-lactam antibiotics, including carbapenems. NDM-1 producing bacterial strains are worldwide threats. It is still very challenging to find a potent NDM-1 inhibitor for clinical use. In our study, we used a metal-binding pharmacophore (MBP) enriched virtual fragment library to screen NDM-1 hits. SPR screening helped to verify the MBP virtual hits and identified a new NDM-1 binder and weak inhibitor A1. A solution NMR study of ¹⁵N-labeled NDM-1 showed that A1 disturbed all three residues coordinating the second zinc ion (Zn2) in the active pocket of NDM-1. The perturbation only happened in the presence of zinc ion, indicating that A1 bound to Zn2. Based on the scaffold of A1, we designed and synthesized a series of NDM-1 inhibitors. Several compounds showed synergistic antibacterial activity with meropenem against NDM-1 producing K. pneumoniae.     

长寿老人源双歧杆菌优良菌株的筛选

以人结肠腺癌细胞系HT-29细胞为试材,对来源于广西巴马百岁以上长寿老人肠道的24株双歧杆菌进行了体外黏附试验。结果发现,双歧杆菌均具有一定的黏附能力,其中TTF、Z2、TZ5和J-1菌株具有较高的黏附能力。进一步对4株初筛双歧杆菌耐胃酸、胆汁酸和合成B族维生素能力的试验发现,双歧杆菌TTF菌株不仅能合成较高的B1、B2、B6、B12等多种B族维生素,而且在pH3．0的条件下处理120min存活率达93．11％,同时在2％胆盐浓度下处理24h有较好的存活,具有显著的综合优势。     

Far‐eastern strains of bean common mosaic virus and methods of their immunodiagnostics

The paper presents data of investigation on the physico‐chemical and antigenic properties of capsid proteins of the Bean common mosaic virus isolated from Phaseolus plants in the Russian Far East (BCMV‐R) and from China (BCMV‐C). A method for isolation of the virus preparation was selected. The purified preparations of two isolates BCMV have been obtained. The presence of one polypeptide in structural proteins of virions was established and their molecular masses determined (BCMV‐R ‐ 31,6 kD; BCMV‐C ‐ 32,1 kD). Polyclonal antiserum was obtained with titre 1:12800 and the indirect and “sandwich"‐variants of ELISA were developed to detect this virus. The allied relationships were established with the bean yellow mosaic virus and with the type representative of the genus Potyvirus ‐ PVY. Based on the data of physico‐chemical and antigenic properties it was concluded that isolates BCMV‐R and BCMV‐C are two independent strains of this virus. The presence of strain‐, virus‐ and genusspecific epitopes of capsid proteine was revealed as a result of comparison of antigenic characteristics of the Russian Far Eastern and Chinese strains of BCMV. A high antigenic activity of capsid protein of the Russian Far Eastern strain was observed.     

Design,synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus

We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure–activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication.     

Rule extraction in gene–disease relationship discovery

Background

Biomedical data available to researchers and clinicians have increased dramatically over the past years because of the exponential growth of knowledge in medical biology. It is difficult for curators to go through all of the unstructured documents so as to curate the information to the database. Associating genes with diseases is important because it is a fundamental challenge in human health with applications to understanding disease properties and developing new techniques for prevention, diagnosis and therapy.

Methods

Our study uses the automatic rule-learning approach to gene–disease relationship extraction. We first prepare the experimental corpus from MEDLINE and OMIM. A parser is applied to produce some grammatical information. We then learn all possible rules that discriminate relevant from irrelevant sentences. After that, we compute the scores of the learned rules in order to select rules of interest. As a result, a set of rules is generated.

Results

We produce the learned rules automatically from the 1000 positive and 1000 negative sentences. The test set includes 400 sentences composed of 200 positives and 200 negatives. Precision, recall and F-score served as our evaluation metrics. The results reveal that the maximal precision rate is 77.8% and the maximal recall rate is 63.5%. The maximal F-score is 66.9% where the precision rate is 70.6% and the recall rate is 63.5%.

Conclusions

We employ the rule-learning approach to extract gene–disease relationships. Our main contributions are to build rules automatically and to support a more complete set of rules than a manually generated one. The experiments show exhilarating results and some improving efforts will be made in the future.     

Discovery of new PPARγ agonists based on arylopeptoids

In this study we present the design, synthesis and biological evaluation of a small, first-generation library of small molecule aromatic amides based on the arylopeptoid skeleton. The compounds were efficiently synthesized using a highly convenient submonomer solid-phase methodology which potentially allows for access to great product diversity. The synthesized compounds were tested for their ability to activate peroxisome proliferator-activated receptors (PPARs) and they all acted as PPARγ agonists in the μM range spanning from 2.5- to 14.7-fold activation of the receptor. This is the first discovery of bioactive molecules based on the arylopeptoid architecture.     

GPGPU加速生物序列比对研究进展

序列比对是生物信息学中最常用和最经典的研究手段。生物序列比对需要有强大计算能力的硬件支撑,而近年快速发展起来的GPGPU正好可堪此任。本文首先介绍GPGPU的发展过程,进而讲述GPGPU硬件设备与其编程环境,然后对GPGPU做科学计算时需要的数学库函数做一介绍,最后综述近年来国内外基于GPGPU的生物序列比对软件和相关研究工作,并总结和展望其辉煌前景。     

河北省三级甲等综合医院图书馆网站建设现状与分析

目的 了解河北省三级甲等综合医院图书馆网站建设的现状。方法 选取河北省22家三级甲等医院网站,采用百度引擎对医院网站进行搜索,对出现的图书馆网站及相关信息进行记录、归类和整理。结果 被调查的22家医院图书馆网站中,7家（33.33%）医院网站无图书馆网站及其相关信息;6家（28.57%）在医院网站主界面设置图书馆链接;8家（38.10%）医院在主网页中科教栏及其他栏目中涵盖图书馆链接,且多数医院图书馆网站信息更新频率慢。结论 河北省三级甲等综合医院图书馆网站建设较为落后,应采取相应措施,促进医院图书馆网站逐步完善。     

Comparison of fractionation proteomics for local SWATH library building

For data‐independent acquisition by means of sequential window acquisition of all theoretical fragment ion spectra (SWATH), a reference library of data‐dependent acquisition (DDA) runs is typically used to correlate the quantitative data from the fragment ion spectra with peptide identifications. The quality and coverage of such a reference library is therefore essential when processing SWATH data. In general, library sizes can be increased by reducing the impact of DDA precursor selection with replicate runs or fractionation. However, these strategies can affect the match between the library and SWATH measurement, and thus larger library sizes do not necessarily correspond to improved SWATH quantification. Here, three fractionation strategies to increase local library size were compared to standard library building using replicate DDA injection: protein SDS‐PAGE fractionation, peptide high‐pH RP‐HPLC fractionation and MS‐acquisition gas phase fractionation. The impact of these libraries on SWATH performance was evaluated in terms of the number of extracted peptides and proteins, the match quality of the peptides and the extraction reproducibility of the transitions. These analyses were conducted using the hydrophilic proteome of differentiating human embryonic stem cells. Our results show that SWATH quantitative results and interpretations are affected by choice of fractionation technique. Data are available via ProteomeXchange with identifier PXD006190.